Krabbe disease: pathology and clinical manifestations

Krabbe Disease

Genetic Components of the Disease

Metabolic Components of the Disease

Causes of the disease

Symptoms of the disease

Diagnosis of the disease

Treatment of the disease

Cord Blood Transfusion

Treatment for Late on-set Form

Gene Therapy

Incidence and Longevity of the disease

Socioeconomic Factors

Krabbe disease, also referred as globoid cell leukodystrophy (GLD), causes a deficiency in galactocerebrosidase (GALC), the enzyme responsible for preventing a build-up of galactolipids in the brain. Without the regulation of galactolipids, the growth of the myelin sheath around the nerve cells is severely impaired. Krabbe disease usually presents in first 6 months of the life. A child in the last stages of Krabbe disease is immobilized and has decreased level of responsiveness. Most of them die at the age of 2. (Lantos, 2011)

Genetic Components of the Disease

GLD is one of the subgroup of metabolic disorders called leukodystrophies. The leukodystrophies are caused by a variety of gene mutations. Gene carries an inherited code of instructions that tells the body how to make every cell and substance in the body. Myelin is damaged due to genetic mutation. Myelin is actually the lip / fat surrounding axon nerve which carries signal to central nervous system.The myelin sheath is similar to the insulation on a wire. It enables the axons to carry signals very quickly. When the myelin sheath is damaged, the signals slow down or may stop completely. Genetic mutation affects an enzyme called galactocerebrodase (GALC) in the patients having GLS which results in the damage of the central nervous system. A person gets the disorder when he or she inherits the gene mutation from both parents. The disease can appear soon after birth (Early on-set Krabbe disease) or in older children or adults (Late on-set Krabbe disease). (Orchard, 2013)

Metabolic Components of the Disease

The metabolic processes of Krabbe are very complicated. As the axon nerve grows, myelin is deformed and broken down over time. The problem in this breakdown will cause the symptoms of lukodystrophy as it affects the nervous system. Galactosylceramide is an important component of myelin sheath and are in fats or lipids in nature. Oligodendrocytes are the synthesizing cells of myelin in the central nervous system and are destroyed when psycho sine (lipid formed due to cerebroside breakdown) is not destroyed.

Causes of the disease

The Krabbe disease is caused when the scavenger cells internalize cerebroside and become large lipid containing "globoid cells." The presence of globoid cells is a critical diagnostic feature of this condition, which is also known as globoid cell Leukodystropy. When tissues from people with Krabbe disease are examined under the microscope these cells can be seen in white matter, as well as the kidney. Persons with this gene defect do not make enough of a substance called galactocerebroside beta-galactosidase (galactosyceramidase)(Rosenberg, 2008).

Symptoms of the disease

The early symptoms of Krabbe that are presented to doctors include:

Changing muscle tone from floppy to rigid.

Hearing loss that leads to deafness.

Feeding difficulties. (Rosenberg, 2008)

Irritability and sensitivity to loud sounds.

Severe seizures.

Unexplained fevers.

Vision loss that leads to blindness.

Vomiting.

The symptoms of late-onset Krabbe disease may include vision problems, followed by walking difficulties and rigid muscles. Symptoms vary from person to person.

Diagnosis of the disease

GLD can be measured by testing a sample of blood or skin cells to measure the activity level of the enzyme GALC. Patients with GLD show very low GALC activity level. A doctor may also do a spinal tap to get the sample of the fluid around the spinal cord. In patients with GLD, the fluid has very high level of protein. Families affected by GLD may want to talk to a genetic counselor about family planning and the chances of having children with the disorder (Orchard, 2013).

To confirm the diagnosis, the doctor might recommend one or more of the following tests:

Imaging scans of the brain and head.

Nerve conduction studies.

Eye examination.

Genetic testing.

Before birth, a fetus can be screened for Krabbe disease. The cells in amniotic fluids are withdrawn from fetus and examined. Diagnosis for Krabbe can also be made examining the activity of GALC enzymes (Orchard, 2013)

Treatment of the disease

Treatment for Krabbe disease depends on which type of disease a person has. The only known treatment that has some effect on the progression of the disease is a bone marrow or cord blood transplant. The healthy cells received in the transplant can make the GALC enzyme which was missing in the body. Though it has serious risks and is not an option for all patients, a transplant can be life- saving and prevent severe disability for some people with GLD (Staff, 2011).

Cord Blood Transfusion

It has been seen that blood transfusion of blood stem cells which are taken form umbilical cord od any unrelated donor can play an important role in the reduction of neurological symptoms in infants. If this is done before the symptoms are appeared, it is possible that the child can maintain his/her vision and hearing ability.

Treatment for Late on-set Form

The people with late on-set Krabbe disease have benefited from treatment with umbilical cord blood stem cells, although this treatment has been most successful in pre-symptomatic patients with the early on-set form of the disease. In cases, where the treatment has been successful, neural deterioration is slowed and symptoms are less severe.

Gene Therapy

Gene therapy is a new method which attempts to provide working copies of genes to people with non-working copies. The DNA sequence of a working gene is placed into the person with an enzyme deficiency. Working enzyme would be made by the person's "new" cells and degrade whatever substance has been stored.

Incidence and Longevity of the disease

In the United States, Krabbe disease affects about 1 in 100,000 individuals. A higher incidence (6 cases per 1,000 people) has been reported in a few isolated communities in Israel.

The Early on-set form of Krabbe disease is usually fatal before the age of two. Those infants who receive cord blood stem cells before the appearance of symptoms have longer lifespans.

Those with Late on-set Krabbe disease usually live between 2 and 7 years after the on-set of symptom. (Tegay, 2012)

Socioeconomic Factors

Taking care of a child with Krabbe disease is a very tough job. It is not possible to do it alone. One has to become a social outcast. Since it does not have a complete cure, therefore the person is completely dependent on others. Some children need therapy even if they get treatment. Some require blood transfusion, which puts an economic pressure too. The cost of treatment is high. It is seen that Krabbe develops more in Israel than population at large. In United States it affects every 1 person in 100,000 populations (Mayo Clinic Staff, 2011). There are many organizations working all over the world to provide support to those who are suffering from Krabbe.